Heterocyclic antiviral compounds

Abstract

This invention relates to piperidine derivatives of formula I wherein R 1 , R 2 , R 3 , R 4 and Y are as defined herein useful in the treatment of a variety of disorders, including those in which the modulation of CCR5 receptors is implicated. Disorders that may be treated or prevented by the present derivatives include HIV and genetically related retroviral infections (and the resulting acquired immune deficiency syndrome, AIDS), rheumatoid arthritis, solid organ transplant reject (graft vs. host disease), asthma and COPR.

1 . A compound according to formula I wherein: 
     
       
         
         
             
             
         
       
       R 1  is selected from the group consisting of (i)-(v) and (vi): 
     
     
       
         
         
             
             
         
       
       
         wherein:
 R 6  is hydrogen, C 1-3  haloalkyl, —N(R a )-A 1 -C(O)R 7  or —NR b R c ; 
 R a  is hydrogen or C 1-3  alkyl; 
 A 1  is C 1-6  straight or branched alkylene; 
 R b  and R c  are (A) together a group (CH 2 ) 2 X 1 (CH 2 ) 2 , or, (B) independently R a  is hydrogen or C 1-3  alkyl and R b  is hydrogen, C 1-3  alkyl, C 1-3  acyl; —SO 2 C 1-6  alkyl or C 1-6  hydroxyalkyl; 
 
       
     
     
       
         
         
             
             
         
       
       
         wherein:
 R 11  is hydrogen, C 3-6  cycloalkyl, cyano, OR 6a  or —O-A 1 -C(O)R 7 ; 
 A 1  is C 1-6  straight or branched alkylene; 
 R 6a  is hydrogen, C 1-3  alkyl or C 1-6  hydroxyalkyl; 
 
       
     
     
       
         
         
             
             
         
       
       
         wherein:
 A 1  is C 1-6  straight or branched alkylene; 
 
       
     
     
       
         
         
             
             
         
       
       
         wherein:
 R 8  is C 3-7  cycloalkyl, (CH 2 ) n COR 7 , —OR 15 , heteroaryl selected from the group consisting of pyridine, pyrimidine, pyrazine and pyridazine said heteroaryl optionally substituted with C 1-3  alkyl or C 1-3  haloalkyl; 
 n is 1 to 3; 
 R 15  is hydrogen or C 1-6  alkoxy; 
 
       
     
     
       
         
         
             
             
         
       
       
         
           wherein: 
           R 16  is hydrogen, hydroxyl or C 1-6  alkoxy; 
         
       
     
     
       
         
         
             
             
         
       
       R 2  is A 2 -R 9 ; 
       R 3  is hydrogen or C 1-6  alkyl; 
       R 4  is C 1-6  alkyl, C 1-6  alkoxy or phenyl; 
       R 7  is hydroxy, C 1-6  alkoxy or NR e R f ; 
       A 2  is (CH 2 ) n , C(O) or S(O) 2  wherein n is an integer from zero to three; 
       Y is O or H,H; 
       R 7  is hydroxyl, NR e R f , or C 1-6  alkoxy; 
       R e  and R f  are (A) together a group (CH 2 ) 2 X 1 (CH 2 ) 2 , or, (B) R e  and R f  are independently hydrogen or C 1-3  alkyl; 
       R 9  is:
 (a) C 3-6  cycloalkyl wherein said cycloalkyl is optionally substituted with one to three groups independently selected from the group consisting of OR 14 , C 1-3  alkyl, oxo, halogen and NR 12 R 13  wherein R 14  is hydrogen, C 1-6  alkyl, C 1-3  alkoxy-C 1-6  alkyl, carbamoyl, C 1-3  alkylcarbamoyl or C 1-3  dialkylcarbamoyl, R 12  is C 1-6  alkylsulfonyl, C 1-6  alkoxycarbonyl or C 1-6  acyl and R 13  is hydrogen or C 1-6  alkyl; 
 (b) heterocyclyl selected from the group consisting of tetrahydropyranyl, tetrahydrofuranyl, oxetanyl, [1,4]dioxanyl, 3-oxa-bicyclo[3.1.0]hex-6-yl or hexahydro-furo[2,3-b]furan-3-yl said heterocycle optionally substituted with one or two C 1-3  alkyl; 
 
     
     
       
         
         
             
             
         
       
       
          wherein;
 p is an integer from one to three; 
 R 10  is C 1-6  acyl, C 1-6  alkoxycarbonyl, C 1-6  alkyl-SO 2 , C 1-6  haloalkyl, C 3-6  cycloalkyl; 
 
         (d) *—NR g R h  wherein:
 (A) R g  and R h  together are (CH 2 ) 2 X 1 (CH 2 ) 2 , (B) together with the nitrogen to which they are attached are C 3-5  alkylene optionally substituted by C 1-3  alkyl, C 1-3  alkoxy, C 1-3  hydroxyalkyl or hydroxy, or, (C) taken independently R g  is hydrogen or C 1-3  alkyl and R h  is hydrogen, C 1-3  alkyl, C 1-3  acyl; —SO 2 C 1-6  alkyl or C 1-6  hydroxyalkyl; 
 
       
       (e) *—OR j  wherein R j  is C 1-6  alkyl or tetrahydropyran-4-yl; 
       (f) C 1-10  alkyl; 
       (g) C 1-10  heteroalkyl; 
       (h) phenyl; 
       (i) pyridinyl; 
       (j) pyrazol-4-yl; 
       (k) imidazolyl;
 wherein said phenyl, pyridinyl, pyrazol-4-yl or imidazolyl are optionally independently substituted with one to three groups independently selected from C 1-3  alkyl, C 1-3  alkoxy, C 3-6  cycloalkyl, halogen, C 1-6  alkoxycarbonyl, carbamoyl, —C 1-6  alkyl carbamoyl, di-C 1-6  alkyl carbamoyl, C 1-6  alkylsulfanyl, C 1-6  alkylsulfinyl or C 1-6  alkylsulfonyl, amino, C 1-3  alkylamino or C 1-3  dialkylamino; 
 
       X 1  is O, S(O) m , NR d ; 
       R d  is hydrogen, C 1-3  alkyl, C 1-3  acyl, C 1-6  alkylsulfonyl; 
       m is zero to two; 
       or, pharmaceutically acceptable salts thereof. 
     
   
   
       2 . A compound according to  claim 1  wherein:
 R 1  is (i) wherein R 6  is hydrogen or (ii) wherein R 11  is cyano;   R 3  is methyl;   R 4  is n-C 4 H 9 ;   A 2  is SO 2 ; and,   R 9  is C 1-6  alkyl, C 3-6  cycloalkyl, phenyl, pyridinyl, tetrahydropyranyl, tetrahydrofuranyl, or NR g R h .   
   
   
       3 . A compound according to  claim 2  wherein R 9  is methyl, cyclopropyl, phenyl, 2-pyridinyl or NR g R h ; and, R g  and R h  are independently are hydrogen or C 1-3  alkyl or together are (CH 2 ) 2 X 1 (CH 2 ) 2 . 
   
   
       4 . A compound according to  claim 3  wherein R 9  is NR g R h  and X 1  is O. 
   
   
       5 . A compound according to  claim 1  wherein:
 R 1  is (i) wherein R 6  is hydrogen or (ii) wherein R 11  is cyano;   R 3  is methyl;   R 4  is n-C 4 H 9 ;   A 2  is SO 2 ; and,   R 9  is (c)   
     
       
         
         
             
             
         
       
     
     wherein R 10  is C 1-6  acyl, C 1-6  alkoxycarbonyl, C 1-6  alkyl-SO 2 , C 1-6  haloalkyl. 
   
   
       6 . A compound according to  claim 1  wherein:
 R 1  is (i) wherein R 6  is hydrogen or (ii) wherein R 11  is cyano;   R 3  is methyl;   R 4  is n-C 4 H 9 ;   A 2  is CH 2 ; and,   R 9  is tetrahydropyran-4-yl, 4-C 1-6  alkoxy-cyclohexyl, 4-fluorophenyl, or:   
     
       
         
         
             
             
         
       
     
     wherein R 10  is C 1-6  acyl, C 1-6  alkoxycarbonyl, C 1-6  alkyl-SO 2 , C 1-6  haloalkyl. 
   
   
       7 . A compound according to  claim 1  wherein:
 R 1  is (i) wherein R 6  is hydrogen or (ii) wherein R 11  is cyano;   R 3  is methyl;   R 4  is n-C 4 H 9 ;   A 2  is C(O); and,   R 9  is tetrahydropyran-4-yl or 4-oxa-tetrahydropyran.   
   
   
       8 . A compound according to  claim 1  selected from the group consisting of: 
     {1-Butyl-9-[1-(4,6-dimethyl-pyrimidine-5-carbonyl)-4-methyl-piperidin-4-yl]-3,9-diaza-spiro[5.5]undec-3-yl}-(tetrahydro-pyran-4-yl)-methanone; 
     5-{4-[7-Butyl-9-(tetrahydro-pyran-4-carbonyl)-3,9-diaza-spiro[5.5]undec-3-yl]-4-methyl-piperidine-1-carbonyl}-4,6-dimethyl-pyridine-2-carbonitrile; 
     [4-(9-Benzenesulfonyl-7-butyl-3,9-diaza-spiro[5.5]undec-3-yl)-4-methyl-piperidin-1-yl]-(4,6-dimethyl-pyrimidin-5-yl)-methanone; 
     1-Butyl-9-[1-(4,6-dimethyl-pyrimidine-5-carbonyl)-4-methyl-piperidin-4-yl]-3-(tetrahydro-pyran-4-ylmethyl)-3,9-diaza-spiro[5.5]undecan-2-one; 
     1-Butyl-9-[1-(4,6-dimethyl-pyrimidine-5-carbonyl)-4-methyl-piperidin-4-yl]-3-(4-fluoro-benzyl)-3,9-diaza-spiro[5.5]undecan-2-one; 
     5-{4-[7-Butyl-8-oxo-9-(tetrahydro-pyran-4-ylmethyl)-3,9-diaza-spiro[5.5]undec-3-yl]-4-methyl-piperidine-1-carbonyl}-4,6-dimethyl-pyridine-2-carbonitrile; 
     {4-[7-Butyl-9-(pyridine-2-sulfonyl)-3,9-diaza-spiro[5.5]undec-3-yl]-4-methyl-piperidin-1-yl}-(4,6-dimethyl-pyrimidin-5-yl)-methanone; 
     [4-(7-Butyl-9-cyclopropanesulfonyl-3,9-diaza-spiro[5.5]undec-3-yl)-4-methyl-piperidin-1-yl]-(4,6-dimethyl-pyrimidin-5-yl)-methanone; 
     1-Butyl-9-[1-(4,6-dimethyl-pyrimidine-5-carbonyl)-4-methyl-piperidin-4-yl]-3-(4-ethoxy-cyclohexylmethyl)-3,9-diaza-spiro[5.5]undecan-2-one; 
     [4-(7-Butyl-9-methanesulfonyl-3,9-diaza-spiro[5.5]undec-3-yl)-4-methyl-piperidin-1-yl]-(4,6-dimethyl-pyrimidin-5-yl)-methanone; 
     1-Butyl-9-[1-(4,6-dimethyl-pyrimidine-5-carbonyl)-4-methyl-piperidin-4-yl]-3,9-diaza-spiro[5.5]undecane-3-carboxylic acid tetrahydro-pyran-4-yl ester; 
     1-Butyl-9-[1-(4,6-dimethyl-pyrimidine-5-carbonyl)-4-methyl-piperidin-4-yl]-3,9-diaza-spiro[5.5]undecane-3-sulfonic acid dimethylamide; 
     {4-[7-Butyl-9-(tetrahydro-pyran-4-sulfonyl)-3,9-diaza-spiro[5.5]undec-3-yl]-4-methyl-piperidin-1-yl}-(4,6-dimethyl-pyrimidin-5-yl)-methanone; 
     {4-[7-Butyl-9-(1-methyl-1H-imidazole-4-sulfonyl)-3,9-diaza-spiro[5.5]undec-3-yl]-4-methyl-piperidin-1-yl}-(4,6-dimethyl-pyrimidin-5-yl)-methanone; 
     5-{4-[7-Butyl-9-(1-difluoromethyl-3,5-dimethyl-1H-pyrazole-4-sulfonyl)-3,9-diaza-spiro[5.5]undec-3-yl]-4-methyl-piperidine-1-carbonyl}-4,6-dimethyl-pyridine-2-carbonitrile; 
     {4-[7-Butyl-9-(1-difluoromethyl-3,5-dimethyl-1H-pyrazole-4-sulfonyl)-3,9-diaza-spiro[5.5]undec-3-yl]-4-methyl-piperidin-1-yl}-(4,6-dimethyl-pyrimidin-5-yl)-methanone; 
     {4-[7-Butyl-9-(tetrahydro-pyran-4-ylmethyl)-3,9-diaza-spiro[5.5]undec-3-yl]-4-methyl-piperidin-1-yl}-(4,6-dimethyl-pyrimidin-5-yl)-methanone; 
     {4-[7-Butyl-9-(morpholine-4-sulfonyl)-3,9-diaza-spiro[5.5]undec-3-yl]-4-methyl-piperidin-1-yl}-(4,6-dimethyl-pyrimidin-5-yl)-methanone; 
     [4-(9-Cyclopropanesulfonyl-7-propoxy-3,9-diaza-spiro[5.5]undec-3-yl)-4-methyl-piperidin-1-yl]-(4,6-dimethyl-pyrimidin-5-yl)-methanone; 
     4-{1-Butyl-9-[1-(4,6-dimethyl-pyrimidine-5-carbonyl)-4-methyl-piperidin-4-yl]-2-oxo-3,9-diaza-spiro[5.5]undec-3-ylmethyl}-piperidine-1-carboxylic acid methyl ester; 
     1-Butyl-3-[1-(2,2-difluoro-ethyl)-piperidin-4-ylmethyl]-9-[1-(4,6-dimethyl-pyrimidine-5-carbonyl)-4-methyl-piperidin-4-yl]-3,9-diaza-spiro[5.5]undecan-2-one; 
     1-Butyl-9-[1-(6-cyano-2,4-dimethyl-pyridine-3-carbonyl)-4-methyl-piperidin-4-yl]-3,9-diaza-spiro[5.5]undecane-3-carboxylic acid tetrahydro-pyran-4-yl ester; 
     1-Butyl-9-[1-(6-cyano-2,4-dimethyl-pyridine-3-carbonyl)-4-methyl-piperidin-4-yl]-3,9-diaza-spiro[5.5]undecane-3-sulfonic acid dimethylamide; 
     4-{1-Butyl-9-[1-(4,6-dimethyl-pyrimidine-5-carbonyl)-4-methyl-piperidin-4-yl]-3,9-diaza-spiro[5.5]undecane-3-sulfonyl}-piperidine-1-carbaldehyde; 
     1-(4-{1-Butyl-9-[1-(4,6-dimethyl-pyrimidine-5-carbonyl)-4-methyl-piperidin-4-yl]-3,9-diaza-spiro[5.5]undecane-3-sulfonyl}-piperidin-1-yl)-ethanone; and, 
     [4-((R)-7-Butyl-9-methanesulfonyl-3,9-diaza-spiro[5.5]undec-3-yl)-4-methyl-piperidin-1-yl]-(4,6-dimethyl-pyrimidin-5-yl)-methanone. 
   
   
       9 . A method for treating or preventing an human immunodeficiency virus (HIV-1) infection, or treating AIDS or ARC, in a patient in need thereof which comprises administering to the patient in need thereof a therapeutically effective amount of a compound according to  claim 1 . 
   
   
       10 . A method according to  claim 9  further comprising co-administering a therapeutically effective amount of one or more compound(s) selected from the group consisting of HIV-1 nucleoside reverse transcriptase inhibitors, non-nucleoside reverse transcriptase inhibitors, HIV-1 protease inhibitors and HIV-1 viral fusion inhibitors and a compound of  claim 1 . 
   
   
       11 . A method for treating an inflammatory disorder comprising administering a therapeutically effective amount of a compound of according to  claim 1  to a patient in need thereof. 
   
   
       12 . A method for according to  claim 11  wherein the inflammatory disorder is rheumatoid arthritis. 
   
   
       13 . A method according to  claim 12  further comprising co-administering a therapeutically effective amount of one or more anti-inflammatory or analgesic compounds and a compound of  claim 1 . 
   
   
       14 . A method for treating asthma or congestive obstructive pulmonary disease (COPD) comprising administering a therapeutically effective amount of a compound according to  claim 1  to a patient in need thereof. 
   
   
       15 . A method for treating solid organ transplant rejection comprising administering a therapeutically effective amount of a compound according to  claim 1  to a patient in need. 
   
   
       16 . A method according to  claim 14  further comprising co-administering a therapeutically effective amount of one or more anti-rejection drugs or immunomodulators and a compound of  claim 1 . 
   
   
       17 . A pharmaceutical composition comprising a compound according to  claim 1  and at least one pharmaceutically acceptable carrier, diluent or excipient.